Little is known about the role of exposure to e-cigarette-related digital content, behavioral and mental health factors, and social environment on the change in adolescent e-cigarette use during COVID-19 shelter-in-place orders and remote schooling. The aim of the study was to examine changes in adolescent e-cigarette use during shelter-in-place and remote schooling in association with exposure to e-cigarette-related digital content and other correlates: stronger e-cigarette dependence, feeling lonely, inability to socialize, e-cigarette use to cope with shelter-in-place, and the number of family members aware of participants' e-cigarette use. A cross-sectional survey conducted between August 2020 and March 2021 included 85 California adolescents (mean age 16.7, SD 1.2 years; 39/85, 46% identified as female and 37/85, 44% as Hispanic) who reported e-cigarette use in the past 30 days. Multivariable penalized logistic regressions determined associations adjusted for age, race and ethnicity, and mother's education. The outcome of increased e-cigarette use was defined as more frequent use of e-cigarettes of the same or stronger nicotine or tetrahydrocannabinol concentration. Almost all respondents (83/85, 98%) reported using social media more since shelter-in-place, and 74% (63/85) reported seeing e-cigarette digital content. More than half (46/85, 54%) reported increased e-cigarette use during shelter-in-place. Most individuals who increased use were exposed to e-cigarette digital content (38/46, 83%) compared to those who did not increase e-cigarette use (25/39, 64%), but the association was nonsignificant after adjusting for demographics (adjusted odds ratio [AOR] 2.34, 95% CI 0.71-8.46). Respondents who felt lonely (AOR 3.33, 95% CI 1.27-9.42), used e-cigarettes to cope with shelter-in-place (AOR 4.06, 95% CI 1.39-13.41), or had ≥2 family members aware of participants' e-cigarette use (AOR 6.42, 95% CI 1.29-39.49) were more likely to report increased e-cigarette use. Almost all participants reported using social media more during shelter-in-place, with many respondents reporting increased e-cigarette use, and significant associations with loneliness and use to cope with shelter-in-place. Future interventions should consider leveraging digital platforms for e-cigarette use prevention and cessation and address the mental health consequences of the COVID-19 pandemic.